PT2010536E - Imidazo [1, 2-b]pyridazines, their processes of preparation and their use as gaba receptor ligands - Google Patents

Description

DESCRIPTION

IMIDAZO [1,2-B] PYRIDAZINES, ITS PREPARATION PROCESSES AND ITS USE AS BINDERS OF GABA RECEPTORS

This invention is directed to agents having affinity for GABA A receptors, specifically imidazo [1,2-b] pyridazine compounds.

BACKGROUND OF THE INVENTION The GABAa receptor (Aγ-aminobutyric acid) is a pentameric protein which constitutes a membrane ion channel. The GABAa receptor is implicated in the regulation of sedation, anxiety, muscle tone, epileptogenic activity and memory functions. These actions are defined by GABAa receptor subunits, particularly al and a2 subunits. Sedation is modulated by the subunit al. Zolpidem is characterized by a high affinity to al receptors and its sedative and hypnotic action is mediated by such receptors in vivo. Likewise, the hypnotic action of zaleplon is also mediated by al. The anxiolytic action of diazepam is mediated by the increase in GABAergic transmission in a population of neurons expressing a2 receptors. This indicates that α2 receptors are highly specific targets for the treatment of anxiety. 1 The muscle relaxation in diazepam is mainly mediated by o2 receptors, since these receptors have a highly specific expression in the spinal cord. The anticonvulsive effect of diazepam is partially due to the Î ± 1 receptors. In diazepam, a compound that impairs memory, and anterograde amnesia is mediated by Î ± 1 receptors. The GABAa receptor and its subunits al and a2 have been extensively reviewed by H. et al. (J. Pharmacol. Exp. There, 300, 2-8, 2002); Möhler H. et al. (Curr Opin Pharmacol., 1, 22-25, 2001); U. Rudolph et al. (Nature, 401, 796-800, 1999) and DJ Nutt et al. (J. Psychiatry Br., 179, 390-396, 2001).

Diazepam and other classic benzodiazepines are widely used as anxiolytic, hypnotic, anticonvulsant and muscle relaxant agents.

Its side effects include anterograde amnesia, decreased motor activity and enhanced effects of ethanol.

In this context, the compounds of the present invention are GABA α α-α 2 receptor linkers for their clinical applicability in sleep disorders, preferably insomnia, anxiety, and epilepsy. Insomnia is a highly prevalent disease. Its chronicity affects 10% of the population and 30% when transient insomnia is also computerized. Insomnia describes difficulty in sleeping or staying asleep, and 2 is associated with hangover effects such as tiredness, lack of energy, low concentration, and irritability. The social and health impact of this complaint is significant and results in obvious socio-economic repercussions. Pharmacological therapy in the treatment of insomnia primarily includes barbiturates and chloral hydrate, but these drugs cause numerous known adverse effects, for example, overdose toxicity, metabolic induction, and increased dependence and tolerance. In addition, they affect the sleep architecture, mainly reducing the duration and number of stages of REM sleep. Later, the use of benzodiazepines meant an important therapeutic advance due to its lower toxicity, but still showed serious problems of dependence, muscle relaxation, amnesia and rebound insomnia after discontinuation of the medication. The last known therapeutic approach was the introduction of non-benzodiazepine hypnotics such as pyrrolo [3,4-b] pyrazines (zopiclone), imidazo [1,2-a] pyridines (zolpidem), and finally pyrazolo [1,5- a ] pyrimidines (zaleplon). Subsequently, two new pyrazolo [1,5-a] pyrimidines], indiplon and ocinaplon, have entered into development, the latter with a little anxiolytic action. All of these compounds present a rapid induction of sleep and have fewer days of effects, less potential for abuse and less risk of rebound insomnia than benzodiazepines. The mechanism of action of such compounds is the allosteric activation of the GABAa receptor through its binding to the benzodiazepine binding site (C.F.P. George, The Lancet, 358, 1623-1626, 2001). Although benzodiazepines are non-specific binding agents at the GABA receptor at the binding site, zolpidem and zaleplon show increased selectivity for the α subunit.

Despite this, these medications still affect the sleep architecture and may induce dependence on long-term treatments.

Some N-imidazo [1,2-b] pyridazine-3-yl-methyl-alkanolamides and N-imidazo [1,2-b] pyridazine-3-yl-methyl-benzamides, wherein the phenyl ring of the benzamide group may optionally substituted, were disclosed in WO89 / 01333.

The compounds of the present invention are structurally related, but distinct from the N, N, 6-trimethyl-2-p-tolylimidazo [1,2-a] pyridine-3-acetamide compound, zolpidem, which is described in US 4,382,938 , because of their improved properties, as shown in the Detailed Description of the Invention. The investigation of new active compounds in the management of insomnia responds to an underlying health need because until recently the introduced hypnotics still affect the sleep architecture and may induce dependence in long-term treatments. It is therefore desirable to concentrate efforts on the development of new hypnotic agents with a lower risk of side effects. 4

SUMMARY OF THE INVENTION The present invention provides novel imidazo [1,2-b] pyridazines which are active against GABAÎ ± and particularly versus the α- and β2 subunits. Thus the compounds of the present invention are useful in the treatment and prevention of all non-limiting examples of such diseases are sleep disorders, preferably insomnia, anxiety and epilepsy. Non-limiting examples of the pertinent indications of the compounds of this invention are all those diseases or conditions , such as insomnia or anesthesia, in which induction of sleep, or induction or sedation or an induction of muscle relaxation are required.

Thus, the present invention describes a novel class of compounds represented by formula (I):

x

and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, and solvates thereof stereoisomers thereof, wherein R1 to R4, and Y are defined below, which are GABAa receptor ligands. It is another object of this invention to provide synthetic procedures for the preparation of the compounds of formula (I), some of their intermediates, as well as intermediates themselves. Novel methods of treating or preventing diseases associated with modulation of GABAÎ ± receptors, such as anxiety, epilepsy and sleep disorders, including insomnia, to induce hypnosis and sedation, anesthesia, sleep, and muscle relaxation by administering a therapeutically effective amount of such compounds are also within the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel imidazo [1,2-b] pyridazine compounds of formula (I):

X

at where

R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched (C1 -C6) alkyl, (C2 -C6) alkenyl, (C2 -C6) alkynyl, (C3 -C6) cycloalkyl, (C2 -C6) haloalkyl, hydroxy, -O- (C1 -C6) alkyl, phenoxy, -S (C1 -C6) alkyl, phenylthio, halogen, nitro, cyano, amino, (C1 -C6) alkylamino, (C1 -C6) dialkylamino, pyrrolidinyl, morpholinyl, piperidinyl, N-C1-6 alkylpiperazinyl, phenyl optionally substituted by 1-5 of the Z groups and heteroaryl optionally substituted by 1-5 of the Z groups; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched (C1 -C6) alkyl, (C2 -C6) alkenyl, (C2 -C6) alkynyl, (C3 -C6) cycloalkyl, (C1 -C6) hydroxyalkyl, amino, -NH- (C1 -C6) alkyl-N-dialkyl (C1 -C6), pyrrolidinyl, morpholinyl, piperidinyl, -N- (C1 -C6) alkylpiperazinyl, -N- (C1 -C6) alkylpiperazinyl, And optionally substituted with 1-5 of the groups Z and heteroaryl optionally substituted by 1-5 of the groups of Z, or both and R3 R4 may form, together with the nitrogen atom to which they are attached, a ring member heterocyclic group optionally substituted by 1-5 of the groups of Z, with the proviso that R3 and R4 may not be simultaneously hydrogen, X is selected from CO and SO2; Z is selected from the group consisting of straight or branched (C 1 -C 6) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 3 -C 6) cycloalkyl, (C 2 -C 6) haloalkyl, (C1 -C6) alkyl, phenoxy, -S (C1 -C6) alkyl, phenylthio, halogen, nitro, cyano, amino, C1 -C6 alkylamino and C1 -C6 dialkylamino, and pharmaceutically acceptable salts, polymorphs, tautomers, solvates and stereoisomers thereof.

Preferably R1 is selected from methyl, chloro, methoxy, ethoxy, phenylthio or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in the para-methyl, halogen, methoxy, nitro or trifluoromethyl position.

Preferably, X is CO; R 3 is selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, phenyl optionally substituted with 1-5 of Z groups, heteroaryl optionally substituted by 1-5 of Z, amino, -NH (C 1 -C 6) alkyl, -N (C1 -C6) dialkyl, a pyrrolidinyl, 4-morpholinyl and 1-piperidinyl; and R 4 is selected from the group consisting of hydrogen, linear (C 1 -C 6) alkyl, phenyl optionally substituted by 1-5 groups Z and heteroaryl optionally substituted by 1-5 groups of Z; or both R3 and R4 may form together with the nitrogen atom to which they are attached, a 5-6 member of the heterocyclic ring 7 optionally substituted by 1-5 groups of Z and Z are selected from the group consisting of methyl and methoxy. The term " pharmaceutically acceptable salt " used herein includes any salt formed from organic and inorganic acids such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, , maleic, malic, malonic, mandelic, methanesulfonic, 1,5-naphthalenesulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic, tartaric, etc.

Preferred compounds of formula (I) include: 2- (6-Chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethylacetamide; 2- (6-Chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 2- (6-Chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-Chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone; N, N-Diethyl-2- (6-pyrrolidin-1-yl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; N, N-Diethyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- [2- (4-Bromo-phenyl) -6-ethoxy-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-acetamide dibutyl; 2- [2- (4-Bromo-phenyl) -6-ethoxy-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; 2- [2- (4-Bromo-phenyl) -6-ethoxy-imidazo [1,2-b] pyridazin-3-yl] -N, N-diethylacetamide; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-morpholin-4-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-acetamide dibutyl; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-dipropyl-acetamide; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-diethylacetamide; 2- [2- (4-Chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-diethylacetamide; 2- [2- (4-Chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-diethylacetamide; 2- [2- (4-Chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-dipropylacetamide; N, N-Dibutyl-2 - [- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [4- (4-Chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] N, N-dipropylacetamide, N, N-Dibutyl-2 - [- 4-chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] acetamide; N, N-Diethyl-2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropyl-acetamide; N, N-Dibutyl-2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-Ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethylacetamide; 2- (6-Ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropyl-acetamide; N, N-Dibutyl-2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-Ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; N, N-Diethyl-2- (6-methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropyl-acetamide; N, N-Dibutyl-2- (6-methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; N, N-Dibutyl-2- [2- (4-fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2- [2- (4-Fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; 10 N, N-Dibutyl-2 - [- (4-fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] N, N-dipropyl-acetamide; N, N-Dibutyl-2- [6-ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] acetamide; 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; N, N-Diethyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazine-3-yl) acetamide; 2- (6-Methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 2- (6-Ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethylacetamide; 2- (6-Ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone; 2- (6-Ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholin-4-yl-ethanone; 2- (6-Ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; N-Diethyl 2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazine-3-yl-acetamide 2- (6-Methyl-2-p-tolyl- 3-yl) -N, N-dipropylacetamide; 11 N, N-Dibutyl-2- (6-methyl-2-p-tolyl-imidazo [1,2- b] pyridazine- 3-yl) acetamide 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone; -2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone 2- (6-Methyl-2-p-tolyl-imidazo [1,2- N, N-Diethyl-2 - [(4-fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; pyridazin-3-yl] acetamide; 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [2- (4-Fluoro-phenyl) -6-methoxyimidazo [1,2-b] pyridazin-3-yl] acetamide; -6-methoxyimidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [ 3-yl] -N, N-diethylacetamide; 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] - 1-piperidin-1-yl-ethanone The; 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; 2- [2- (4-Fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; N, N-Diethyl-2 - [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2-2 [- (4-Methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropylacetamide; N, N-Dibutyl-2 - [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2-2 [- (4-Methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 12 2-2 [- (4-Methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; N, N-Diethyl-2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [6-Methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; N, N-Dibutyl-2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [6-Methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [6-Methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; 2 - {[2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetyl-propyl-amino} -ethyl ester; 1- (3,5-Dimethyl-piperidin-1-yl) -2-6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) ethanone; N-Cyclopropylmethyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-propylacetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-thiazol-2-yl-acetamide; N, N-Disopropyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; N-Cyclohexyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-phenyl acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -NP-tolyl-acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-pyridin-2-yl-acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-pyridin-2-ylmethyl-acetamide; 13β- (3,5-Dimethyl-isoxazol-4-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide, N-Cyclopentyl -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; N, N-Diallyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; N-Cyclopropyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-hydroxy-2-yl-acetamide; N- (5-Methylisoxazol-3-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; N- (4-Methoxy-phenyl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; N- (3-Methylisoxazol-5-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N- [1,3,4] thiadiazol-2-yl-acetamide; [2- (4-Fluoro-phenyl) -6-pyrrolidin-1-yl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; [2- (4-Bromo-pheno) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; [2- (4-Methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; [2- (4-Chloro-phenyl) -6-methyl-imidazo [1,2-bpyridazin-3-yl] -hydrazide; [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; pyridazin-3-yl) -N-morpholino-4-acetamide; 2 2- (6-Methyl-2-p-tolyl-imidazo [1,2- b] pyridazin- 1-yl-acetamide, and (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetic acid N ', N'-dimethylhydrazide.

Another aspect of the present invention is to provide a process for the preparation of compounds of formula (I), as well as an intermediate imidazo [1,2-b] pyridazine of formula (II):

where R is methyl, R 1 is methyl, chloro, methoxy, ethoxy, thiophenoxy or 1-pyrrolidinyl group and R 2 is a phenyl group or a phenyl group substituted in the para-position by methyl, halogen, methoxy, nitro or trifluoromethyl.

The compounds of formula (I), when X is CO, may be obtained following the synthetic strategy shown in Scheme 1.

Scheme 1

From ketoacids (III), ketoamides (IV) can be obtained by standard coupling conditions. These ketoamides (IV) may be brominated at the α-position of the carbonyl group by reaction with bromine in acetic acid to yield the bromoketoamides (V). Finally, the cyclization of aminopyridazine (VI) in refluxing acetonitrile allows the imidazopyridines (I, X = CO).

On the other hand, if R 3 or R 4 are optionally substituted amino groups, then the obtained molecule is not an amide but a hydrazide. The synthetic route has to be slightly modified for this proposal (Scheme 2). 16

Scheme 2

Fischer esterification of the same ketoacid (III) is carried out with an alcohol ROH to provide the corresponding ester (VII). This ester is brominated under conditions similar to those of the starch (IV) described above, for the production of bromoketoesters (VIII). Cyclization with aminopyridazines (VI) allows the preparation of imidazopyridines (II) substituted with an ester group. Finally, acrylic substitution using a substituted hydrazine in a reflux solvent gives the corresponding hydrazides (I, X = CO, R 3 or R 4 are optionally substituted amino groups). Suitable solvents for use in this reaction are preferably straight or branched C 1 -C 6 alkanes, more preferably methanol, or mixtures thereof. 17

The compounds of the present invention or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, and stereoisomeric solvates may be used for the preparation of a medicament for treating or preventing diseases associated with GABAÎ ± receptor modulation in a human or non-human mammal. More specifically, diseases associated with GABAÎ ± receptor modulation include diseases associated with α-i-GABAA receptor modulation and / or α-2-GABAA receptor modulation. It is known by the art in the art that the diseases associated with modulation of the GABAa receptor are (" Compartmentation of alpha 1 and alpha 2 GABAA receptor subunits within rat extended amygdala: implications for benzodiazepine action ", Science 2003, vol 964 p.91- 99; Möhler H. et al., &Quot; GABAA receptor subtypes: a new pharmacology ", Current Opinion in Pharmacology 2001, vol.1: 22-25). A non-exhaustive list of such diseases includes anxiety, epilepsy, sleep disorders, including insomnia, and so on.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate and stereoisomer thereof for the preparation of a medicament for treating or preventing anxiety in a human mammal or not human.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in the treatment or prevention of anxiety in a human or non-human mammal. 18

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomers thereof for the preparation of a medicament for treating or preventing epilepsy in a human mammal or non-human who need it.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in the treatment or prevention of epilepsy in a human or non-human mammal.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for treating or preventing sleep disorders in a human or non-human mammal in need thereof.

This aspect can be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in the treatment or prevention of sleep disorders in a mammalian human or non-human.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for treating or preventing insomnia in a mammal human or non-human who need it.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in the treatment or prevention of insomnia in a human or non-human mammal.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for inducing sedation hypnosis in a human mammal or non-human who need it.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrates, tautomer, solvate or stereoisomer thereof for use in the induction of sedation hypnosis in a human or non-human mammal.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for inducing anesthesia in a human or mammals that need it.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in inducing anesthesia in a human or non-human mammal.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for modulating the time required to induce sleep and their duration in a human or non-human mammal in need thereof.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in modulating the time required to induce sleep and its duration in a human or non-human mammal who need it.

Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for inducing muscle relaxation in human or non-human who need it.

This aspect may be reformulated as a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for use in inducing muscle relaxation in a human or non-human mammal in need thereof. The present invention also relates to compounds of formula (I) to be used in a method of treating or preventing the suffering of a human or non-human mammal from diseases associated with GABAÎ ± receptor modulation in a human or non-human mammal, comprising administering to said human or non-human mammal a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof together with pharmaceutically acceptable diluents or carriers. More specifically, diseases associated with GABAÎ ± receptor modulation include diseases associated with Î ± -1 GABAÎ ± receptor modulation and / or α-2-GABAÎ ± receptor modulation. The non-exhaustive list of such diseases includes anxiety, epilepsy, sleep disorders, including insomnia, and so on.

As used herein, the term " mammal " refers to the class of higher vertebrate mammals. The term " mammal " includes, but is not limited to, a human being.

As used herein, " term " refers to the class of higher vertebrate mammals. The term " mammal " includes, but is not limited to, a human being.

Another embodiment of the present invention is to provide a pharmaceutical composition containing a compound of formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof in association with therapeutically inert carriers.

The compositions include those suitable for oral, rectal and parenteral (including subcutaneous, intramuscular, intravenous) administration, although the most suitable route depends on the nature and severity of the condition being treated. The preferred route of the present invention is the oral route. The compositions may conveniently be presented in unit dosage form, and prepared by any of the methods known in the pharmaceutical art. The active compound may be combined with a pharmaceutical carrier according to conventional pharmaceutical manipulation techniques. The carrier may take a wide variety of forms, depending on the type of preparation desired for administration, for example, oral or parenteral (including intravenous injections or infusions). In preparing the compositions for the oral dosage form of any of the usual pharmaceutical means may be employed. Usual pharmaceutical means include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and the like, in the case of liquid oral preparations (eg suspensions, solutions, emulsions and elixirs); aerosols; or carriers, such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of solid oral preparations (such as powder, capsules and tablets) with the solid preparations oral formulations of liquid oral preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous form of oral dosage unit, in the case where solid pharmaceutical carriers are employed. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques.

A large dosage suitable for use is from about 0.01 mg to about 100.00 mg total daily dose given as a single daily administration or in divided doses if necessary.

The compounds of the present invention have a high affinity for α 1 and α 2 GABAa receptors. These in vitro results are consistent with in vivo results obtained in hypnosis-sedation tests.

In accordance with the results obtained, certain compounds of the present invention have proven in vitro and in vivo pharmacological activity, which was similar or greater than the prior art compound zolpidem. All these results support its use modulated by α1 and α2 GABAα receptors such as insomnia or anesthesia, in which induction of sleep, induction of sedation or induction of muscle relaxation is required. The pharmacological activity of the compounds of the present invention was determined as shown below. a) Ligand binding assays. Determination of the test compounds for al 1 and a 2 GABAa receptors

Male Sprague-Dawley mice weighing 200-250 g were used at the time of the experiment. After decapitation of the animal, the cerebellum (tissue containing mainly GABAa a 1 receptors) and the spinal cord (tissue containing mostly GABAa α 2 receptors) were removed. The membranes were prepared according to the method of J. Lameh et al. (Prog. Neuro-Psychopharmacol Biol. Psychiatry, 24, 979-991, 2000). Once the tissues were weighed, they were suspended in 50 mM Tris.HCl (pH 7.7), 1:40 (v / v), homogenized and then centrifuged at 20,000 g for 10 min at 7øC. The resulting pellet was resuspended under the same conditions and again centrifuged. The pellet was finally resuspended in a minimum volume and maintained at -80 ° C overnight. A slight modification was used in the case of the spinal cord in the first centrifugation phase. The centrifugation rate was 1000æg and the supernatant was collected rather than discarded as in the cerebellum. Thereafter, the supernatant was centrifuged at 20000 g and resuspended twice under the same conditions described above for cerebellum.

The next day, the process was repeated until the final pellet was resuspended in a ratio of 1:10 (v / v) in the case of the cerebellum and in the ratio of 1: 5 (v / v) in the case of the vertebral column. Affinity was determined by competitive assays using as radiolabeled flumazenil ligand. The tests were conducted according to the methods described by S. Arbilla et al. (Eur. J. Pharmacol., 130, 257-263 1986); and Y. Wu et al. (Eur. J. Pharmacol., 278, 125-132 1995) using microtiter plates 96. Membranes containing the study receptors, flumazenil (radiolabeling at a final concentration of 1 nM) and ascending concentrations of test compounds (in a volume Total 230 pL in 50 mM [pH 7.4] Tris.HCl buffer were incubated. Simultaneously, the membranes were incubated only with radiolabeled flumazenil (total binding, 100%) and in the presence of a high concentration of non-flumazenil (non-specific binding, estimate of% radiolabelled ligand) Reactions were initiated by the addition of the radioactive ligand followed by an incubation for 60 minutes at 4 ° C. At the end of the incubation period, 200 μl reaction were transferred to a multiscreen plate (Millipore) and filtered through a vacuum dispenser and then washed three times with cold test buffer. equipped with GF / B filter that retained the membranes containing the receptors of the radioactive ligand that had been bound to the receptors. After washing, the plates were allowed to dry. Once dried, scintillation liquid was added and left to stir overnight. The next day, the plates were counted using a Perkin-Elmer Microbeta scintillation counter.

For analysis of the results the percentage of specific binding for each concentration of the test compound was calculated as follows:% for specific binding = (X-N / T-N) x 100 wherein, X: total amount of bound ligand for each concentration of compound. T: total binding, maximum bound amount of radiolabeled ligand. N: non-specific binding, amount of radiolabeled ligand in a nonspecific manner regardless of the receptor used. 26

All compound concentrations were tested in duplicate and their mean values were used to determine the experimental values of specific binding% relative to the compound concentration. Affinity data are expressed as% inhibition at 10-5M and 10-7M concentrations. The results of these tests are presented in Tables 1 and 2. 27

Table 1. Affinity to the α-subunit of the GABAα receptor

Compound% inhibition 10-5M% inhibition 10-7M Example 1 100.1 98.2 Example 2 100.3 9 9.6 Example 3 100.2 99.4 Example 499.9 98.3 Example 5 100.3 97.5 Example 6 100.0 97.4 Example 9 96.8 11.4 Example 10 99.1 39.3 Example 11 96.0 22.0 Example 12 9 6.9 34.6 Example 13 99. 7 58.3 Example 14 99.5 80.6 Example 17 99.5 97.1 Example 20 9 9.6 73.7 Example 22 100.0 97.6 Example 23 99.1 61.7 Example 24 98.4 57.7 Example 26 100.0 73.5 Example 35 100.2 97.5 Example 40 100.3 98.0 Example 41 99.8 75.4 Example 42 99. 7 62.2 Example 43 99.5 49.9 Example 65 99.5 58.5 Example 66 98.3 50.4 Example 67 98.9 42.2 Example 70 9 9.9 84.5 28 (Continued)

Example 71 Example 72 Example 73 Example 75 Example 77 Example 78 Example 80 Example 81 Example 82 Example 83 Example 84 Example 86 Example 87 Example 88 Example 91 Example 93 Example 94 Example 100 Example 102 Example 105 Example 106 Zolpidem. 2 95.0. 4 91.5 9 76.5 4 52.1. 1 42.2 3 26.5 7 85.2. 1 98.5. 1 99.2 6 97.6. 0 91. 7 5 75.9 3 57.2. 2 83.9 1 45.8. 0 78.2. 1 65.1 LO 62.4 1 66.7 CO 56.0 5 53.7 4 73.6 29

Table 2. Affinity to the α-subunit of the GABAα receptor

Compound% inhibition% inhibition 1CT5M 1CT7M Example 1 94.3 49.0 Example 2 98.6 6 6.1 Example 3 91.3 60.8 Example 4 97.6 53.2 Example 5 97.7 45.0 Example 6 97.5 49.4 Example 9 61.7 5.9 Example 10 72.0 19.1 Example 11 47.0 1. 7 Example 12 71.9 2.2 Example 13 76.7 15.5 Example 14 76.9 10.8 Example 17 83.0 36.8 Example 20 82.0 20.8 Example 22 86.6 61.2 Example 23 80.0 0.0 Example 24 77.4 13.6 Example 26 84.5 27.4 Example 35 92.5 57.9 Example 40 91.5 60.7 Example 41 85.3 17.0 Example 42 79.4 16.3 Example 43 80.3 20.1 Example 65 78.5 16.3 Example 66 79.4 7.8 Example 67 83.7 8.8 Example 70 80.3 23.6 Example 71 88.5 50.6 30 (Continued)

Example 72 85.6 51.7 Example 73 77.0 20.6 Example 75 68.8 9.3 Example 77 83.4 23.6 Example 80 84.3 37.0 Example 83 93.1 57.7 Example 84 63.9 3.1 Example 86 80.9 23.0 Example 100 73.0 2.3 Example 102 77.9 13.7 Zolpidem 74.1 19.9 b) In vivo determination of the action sedative-hypnotic predictive

The in vivo effects of these compounds were assessed by a predictive sedation-hypnosis test (DJ Sanger et al., Eur. J. Pharmacol., 313, 35-42, 1996; and G. Griebel et al., Psychopharmacology, 146 , 205-213, 1999).

Groups of 5-8 male CD1 mice weighing 22-26 g were used at the time of the test. The test compounds were administered in single intraperitoneal equimolecular doses, suspended on 0.25% agar with one drop of Tween in a volume of 10 ml / kg. Control animals received only the vehicle. Using an Actisystem DAS16 (Panlab, S.L., Spain), the number of passages (counts) was recorded for each mouse at 5 minute intervals over a 30 minute period after dosing. Inhibition of the percentage of distance traveled from treated animals 31 versus control animals (the first 5 minutes were discarded) was calculated. Some compounds were also tested at a low dose - 0.98 ymol / kg - to later discriminate the potency of induction of sedation. The results of this test are given in Table 3 and Table 4.

Table 3. In vivo determination of sedative-hypnotic activity in mice at 98.0 and mol / kg

Compound% inhibition of motor activity Example 1 94.66 Example 2 96.71 Example 3 90.94 Example 4 94.65 Example 5 93.65 Example 6 96.86 Example 9 93.85 Example 10 93.47 Example 11 79.82 Example 12 83.44 Example 13 92.08 Example 14 95.56 Example 17 93.08 Example 20 91.51 Example 22 87.97 Example 23 91.74 Example 24 86.54 Example 26 91.55 Example 35 80.60 Example 40 91.79 Example 41 91.18 32 (Continued)

Example 42 91.01 Example 43 95.72 Example 65 95.46 Example 66 95.95 Example 67 90.81 Example 70 86.98 Example 71 95.96 Example 72 93.35 Example 73 94.07 Example 75 92.56 Example 77 89.35 Example 78 91.14 Example 80 94.41 Example 81 90.83 Example 82 94.22 Example 83 88.93 Example 84 90. Example 86 92.62 Example 87 90. Example 88 88.51 Example 91 93.05 Example 93 93.20 Example 94 93.49 Example 100 93.71 Example 102 85.50 Example 105 94.02 Example 106 94.05 Zolpidem 91. 70 33

Table 4. In vivo determination of hypnotic sedative activity in mice at 98.0 pmol / kg

Compound% inhibition of motor activity Example 1 27.56 Example 2 38.39 Example 3 14.61 Example 4 38.38 Example 5 41.15 Example 6 51.90 Example 9 19.94 Example 10 29.54 Example 11 15.29 Example 12 15.05 Example 13 15.11 Example 14 4.77 Example 17 9.91 Example 22 22.21 Example 23 12.37 Example 24 3.65 Example 26 19.19 Example 35 6.76 Example 41 15.73 Zolpidem 18.30 c) In the in vivo determination of predictive anesthetic activity

The in vivo effects of these compounds were evaluated by a predictive test of anesthesia in mice such as loss of righting reflex (Kralic et al., Neuropharmacology, 43 (4), 685-689 2002; Belelli et al., Neuropharmacology, 45, 57-71, 2003).

Groups of 5-8 male CD1 mice, weighing 22-26 g at the time of the test, were used. Test compounds were administered at 98.0 Âμmol / kg by intraperitoneal injection. Compounds were suspended in 0.25% agar with one drop of Tween in a volume of 10 mUkg. The percentage of treated rats which had loss of righting reflex was calculated.

Interestingly, compounds of Examples 2, 3, and 82 showed 90%, 100% and 30% of animals with loss of righting reflex, respectively. Unlike zolpidem, the prior art compound, presented lower anesthetic potential, it being necessary to administer double dose of compounds of the present invention to achieve 80% of animals with loss of righting reflex. d) Comparative test

In order to demonstrate that the compounds of the present invention are better than others known in the art, especially those described in PCT application WO 89/01333, the IC 50 value for compounds 22, 26, 88, 95, 96, 97 and 98 were calculated and compared with the structurally related compounds described in said PCT application, ie, compounds 317 and 318. All of these compounds have in common the fact in position 3, imidazo [1,2-b] pyradizine ring ter acetamide. The remaining compounds disclosed in WO89 / 01333 are not structurally related to the compounds of the present invention.

IC 50 values were estimated from the Cheng-Prusoff equation (Cheng YC and Prusoff WH; Biochem Pharmacol 22, 3099-3108, 1973)

Ki 1 + IC 50Kd where,

Ki is determined for each of the compounds of the invention as described above (section (a)).

[RL *]: concentration of radioactive labeling of ligand (1 nM).

Kd: affinity constant (cerebellum 1.34nM / spinal cord 1.19nM). Guideline 5 shows the IC 50 values obtained for the compounds of the present invention and includes the IC50 values for compounds 317 and 318 of PCT application WO89 / 01333: 36

COMPOUNDS OF THE INVENTION Number of example ICso (nM) 22 17.2 88 13 95 17.1 97 14.6 98 12.2 COMPOUNDS OF WO89 / 01333 317 55 318 474

As it is derived from the results obtained, the compounds of the present invention have IC50 values lower than the IC50 values WO89 / 01333, which means that a lower dose of the compounds of the present invention is necessary to achieve the same therapeutic effects.

The following non-limiting examples illustrate the scope of the present invention.

Example A. General method for the preparation of starches (IV)

To a solution of the acid (III) (1eq) in dichloromethane was added to a solution of water-soluble carbodiimide (1.537 eq) in dichloromethane. The mixture was stirred at room temperature for 30 minutes. After this period, a solution of 0.5 eq of 4-dimethylamino pyridine and 1.5 eq of the corresponding amine in dichloromethane was added, and the mixture was stirred for 6 h. The crude was washed with 1N HCl, the organic layer was dried over Na2 SO4, filtered and the solvent was removed in vacuo to afford ketoamide (IV).

For example, for

1 H NMR (400 MHz, DMSO-d 6): δ 7.80-7.15 (m, 4H, Ar), 3.30 (t, 4H, CH 2 N), 2.87 (t, 2H, CH 2 CO), 2.47 (t, 2H, 1.58-0.93 (m, 14H, CH 2 CH 2 CH 3). MS (ES) m / z = 308 (MH +) HPLC = 100%

Yield = 80%

Example B: General method for the preparation of bromoamides (V, X = CO)

38

To a solution of (IV) (1eq) acetic acid was added drops of a solution of bromine (2.2eq) in acetic acid. The mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / 1N NaOH and dichloromethane / water. The organic layer was dried over Na2 SO4 and filtered, and the solvent was removed under vacuum, thus allowing bromoketoamide (V).

For example, for

1 H NMR (400 MHz, DMSO-d 6): δ 7.97-7.23 (m, 4H, Ar), 5.20 (t, 2H, CHBr), 3.24 (t, 4H, CH 2 N), 2.87 (d, 2H, CH 2 CON), 1.75-0.76 (m, 14H, CH 2 CH 2 CH 3). MS (ES) m / z = 380 (M), 382 (M + 2H) HPLC = 95%

Yield = 34%

Example C: General method for the preparation of imidazopyridines (I, X = CO)

(V, X * CO)

To a solution of (V) (1eq) in acetonitrile was added a solution of (VI) (1.2 eq) in acetonitrile. The mixture was stirred at reflux for 2 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / 1N HCl and DCM / water. The organic layer was dried with Na2 SO4 and filtered, and the solvent was removed under vacuum, thus allowing the imidazopyridazine (I).

For example, for

NMR (400 MHz, DMSO-d 6): δ 7.30-7.03 (m, 6H, Ar), 3.48 (s, 2H, CH 2), 2.32 (s, 3H, CH 3), 3.21-0.96 (m, 18H, CH 2 CH 2 CH 2 CH 3 ). MS (ES) m / z = 397 (MH +) HPLC = 89%

Yield = 60%

Compounds 1-98 were prepared according to this methodology.

Example number MH + (LCMS) Purity (UV) IUPAC NAME 1 358 99 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethyl-acetamide 2 386 99 N, N-Dibutyl-2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide (Continued)

Example No. MH + (LCMS) Purity (UV) IUPAC NAME 3 414 97 2- (6-chloro-2-p-tolyl-imidazo [1,2- b] pyridazin-3-yl) -N, N-dipropyl- acetamide 4 370 94 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone -2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone 6- (6-chloro-2-p-tolyl-imidazo [ 1-yl-ethanone 7 393 100 N, N-diethyl-2- (6-pyrrolidin-1-yl-2-p-tolyl-imidazo [ N-diethyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide 9 446 84 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b]] pyridazine-3-yl-1-morpholino-4-yl-ethanone 10 444 100 2- [ 2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b]] pyridazin-3-yl-1-piperidin-1-yl-ethanone 11 488 100 2- [2- (4-Bromo- -phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-dibutylacetamide (Continued)

Example No. MH + (LCMS) Purity (UV) IUPAC NAME 12 460 100 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2- b] pyridazin-3-yl] N-dipropylacetamide 13 432 80 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-diethylacetamide 14 416 86 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b]] pyridazin-3-yl-1-morpholino-4-yl-ethanone 15 414 96 2- Bromo-phenyl) -6-methyl-imidazo [1,2-b]] pyridazin-3-yl-1-piperidin-1-yl-ethanone 16 458 99 2- [2- (4-Bromo-phenyl) -6- -methyl-imidazo [1,2-b] pyridazin-3-yl] -N, N-dibutylacetamide 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [ 2-b] pyridazin-3-yl] -N, N-dipropylacetamide 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2- b] -pyridazine- 3-yl] -N, N-diethylacetamide 19 358 94 2- [2- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] -pyridazin-3-yl] -N, N- diethylacetamide 20 388 87 2- [2- (4-chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-diethylacetamide (Continued)

Example No. MH + (LCMS) Purity (UV) IUPAC NAME 21 386 100 2- [2- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] -pyridazin-3-yl] -N- , N-dipropylacetamide 22 414 99 N, N-Dibutyl-2 - [- (4-phenyl chloro) -6-methyl-imidazo [1,2- b] pyridazin-3-yl] acetamide 23 416 98 2- [2- (4-chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-dipropylacetamide 24 444 100 N, N-Dibutyl-2- [ - (4-chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] acetamide 25 339 80 N, N-Diethyl-2- (6-methoxy-2-phenylimidazo [ 1,2-b] pyridazin-3-yl) acetamide 2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide 396 87 2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide 28 353 100 2- (6-methoxy- 1,2-b] pyridazin-3-yl) -1-morpholin-4-yl-ethanone 2- (6-Ethoxy-2-phenylimidazo [1,2- b] pyridazin-3-yl) - N, N-methyl-acetamide (Continued)

Example number MH + (LCMS) Purity (UV) IUPAC NAME 30 381 100 2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone 2- (6-Ethoxy-2-phenyl-imidazo [1,2- b] pyridazin-3-yl ) -1-piperidin-1-yl-ethanone 34 323 80 N, N-Diethyl-2- (6-methyl-2-phenylimidazo [1,2-b] -3-pyridazin-3-yl) acetamide 351 100 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide N, N-Dibutyl-2- (6-methyl -2-phenylimidazo [1,2-b] pyridazin-3-yl) acetamide 2- (6-Methyl-2-phenylimidazo [1,2- b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone 38 (Methyl 2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone Continuation)

Example No. MH + (LCMS) Purity (UV) IUPAC NAME 39 369 89 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] -pyridazin-3-yl] -N- , N-dipropylacetamide 40 398 89 N, N-Dibutyl-2 - [- (4-fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazine-3-yl] acetamide 41 385 90 2 - [2- (4-Fluoro-phenyl) -6-methoxy-imidazo [1,2-b] -pyridazin-3-yl] -N, N-dipropyl-acetamide N, N-Dibutyl- [4- (4-fluoro-phenyl) -6-methoxyimidazo [1,2-b] pyridazine-3-yl] acetamide 43 399 85 2- [6-Ethoxy-2- (4-fluoro-phenyl) [1,2-b] pyridazin-3-yl-N, N-dipropylacetamide N, N-Dibutyl-2- [6-ethoxy-2- (4-fluoro-phenyl) -imidazo [ , 2-b] pyridazin-3-yl] acetamide 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-morpholino -4-yl-ethanone 46 353 97 N, N-Diethyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazine-3-1) acetamide 47 381 82 2 - 6-methoxy-2-p-tolyl-imidazo1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide (Continued)

N-Dibutyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide 2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone 2- 2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethyl-acetamide 2- (6-Ethoxy- b] pyridazine-3-yl) -N, N-dipropylacetamide N, N-Dibutyl-2- (6-ethoxy-2-p-tolyl-imidazo [1,2- b] yl) acetamide 2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidine 1-yl-ethanone 2- ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone 2- (6-Ethoxy- N-diethyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone b] pyridazin-3-yl) acetamide (Continued)

Example No. MH + (LCMS) Purity (UV) IUPAC NAME 57 365 90 2- (6-Methyl-2-p-tolyl-imidazo [1,2- b] pyridazin-3-yl) -N, N-dipropyl- acetamide 58 394 90 N, N-Dibutyl-2- (6-methyl-2-p-tolyl-imidazo [1,2- b] pyridazin-3-yl) acetamide 2- (6-Methyl- p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone 2- (6-Methyl-2-p-tolyl-imidazo [ b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone 61 349 85 2- (6-Methyl-2-p-tolyl-imidazo [1,2- b] pyridazin-3-yl) -1- piperidine-1-yl-ethanone 62 341 87 N, N-Diethyl-2 - [- (4-fluoro-phenyl) -6-methyl-imidazo [1,2- b] pyridazin-3-yl] -acetamide 63,353 81 2- [4- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b]] pyridazin-3-yl-1-piperidin-1-yl-ethanone N, 2- [4- (4-Fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] -imidazo [1,2-b] -3-pyridazin-1-yl] -1-piperidin-1-yl-ethanone (Continued)

2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] -pyridazin-3-yl] -N- , N-diethylacetamide 67 383 91 2- [6-ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b]] pyridazin-3-yl-1-morpholin-4-yl-ethanone 4-Fluoro-phenyl) -6-methoxyimidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone 70 353 99 N, N-Diethyl-2- [2- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -acetamide 2-2 [- (4-methoxy-phenyl) -6-methyl-imidazo [ , 2-b] pyridazin-3-yl] -N, N-dipropylacetamide 72 410 100 N, N-Dibutyl-2 - [- (4-methoxyphenyl) -6-methyl-imidazo [1,2- -b] pyridazine-3-yl] acetamide 2-2 [- (4-methoxy-phenyl) -methyl-6-imidazo [1,2-b] -pyridazin-3-yl] -1- 1-yl-ethanone 2-2 [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] -pyridazin-3-yl] -1-morpholin-4-yl-ethanone 48 (Continued)

N-Diethyl-2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazine-3 -yl] acetamide 76 397 98 2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] -pyridazin-3-yl] -N, N-dipropyl-acetamide 77 426 100 N-Dibutyl-2- [6-methoxy-2- (4-methoxyphenyl) imidazo [1,2-b] pyridazin-3-yl] acetamide 2- [6-methoxy- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -piperidine-11-yl-ethanone 2- [6-methoxy-2- (4-methoxyphenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone 80 410 94 Acetic acid 2 - {[2- (6-methyl-2-.beta.- 3-yl) -acetyl-propylamino} -ethyl ester 81 1- (3,5-Dimethyl-piperidin-1-yl) -2- (6-methyl-2-p- 3-yl) -ethanone 82 378 93 N-cyclopropylmethyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazine-3 -yl) -N-propylacetamide 2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-thiazole-2-yl-acetamide (Continuation)

N-Diisopropyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide N-Cyclohexyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide 2- (6-methyl-2-p- tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-phenylacetamide 2- (6-methyl-2-p-tolyl-imidazo [1,2- b] pyridazin-3-yl) N-tolyl acetamide 88 358 96 2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-pyridin-2-yl-acetamide 89 372 94 2 - (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-pyridine-2-acetamide-1-methyl 90 376 99 N- (3,5- isoxazol-4-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide N-cyclopentyl-2- (6-methyl-2- -β-tolyl-imidazo [1,2-b] -3-pyridazin-1-yl) acetamide N, N-diallyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b ] -pyridazin-3-yl) acetamide (Continued)

Example number MH + (LCMS) Purity (UV) IUPAC NAME 93 321 97 N-cyclopropyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide 408 95 2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-hydroxy-2-yl-acetamide 95 362 95 N- (5-methylisoxazole -3-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide N- (4-methoxy-phenyl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide N- (3-methylisoxazol-5-yl) -2- (6-methyl -2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide 2- (6-methyl-2-p-tolyl-imidazo [1,2- b] pyridazine-3 -yl) -N- [1,3,4] thiadiazol-2-yl-acetamide

Example D: General method for the preparation of keto esters (VII)

51

To a solution of (III) (1eq) in methanol (ROH, R = CH3) was added dropwise a solution of concentrated H2 SO4 (0.5 eq) in methanol. The mixture was stirred at reflux for 30 minutes. The solvent was removed in vacuo and the residue was extracted with dichloromethane / 1N NaOH and dichloromethane / water. The organic layer was dried over Na2 SO4 and filtered, and the solvent was removed under vacuum, thus allowing the ketoester (VIII).

For example, for

D

NMR (400 MHz, DMSO-d 6): δ 7.89-6.88 (m, 4H, Ar), 3.75 (s, 3H, OCH 3), 3.77 (s, 3H, OCH 3), 2.65 (t, 2H, CH 2 CO), 2.25 (t, 2H, CH2 COO). MS (ES) m / z = 223 (MH +) HPLC = 95%

Yield = 93%

Example E: General method for the preparation of bromoketoester (VIII)

(VII)

To a solution of (VII) (1 EQ) in acetic acid was added dropwise a solution of bromine (2.2 eq) in acetic acid. The mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / 1N NaOH and dichloromethane / water. The organic layer was dried with Na2 SO4 < 4 > and filtered, and the solvent was removed under vacuum, thus allowing the bromoketoester (VIII).

1 H NMR (400 MHz, DMSO-d 6): δ 7.98-6.82 (m, 4H, Ar), 5.38 (t, 1H, CHBr), 3.98 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), 2.75 (t, 2H, CH2 COO). MS (ES) m / z = 301 (M), 303 (M + 2H) HPLC = 95% Yield = 35%

Example F: General method for the preparation of imidazopyridines (II)

53

To a solution of (VIII) (1eq) in acetonitrile was added a solution of (VI) (1.2eq) in acetonitrile. The mixture was stirred at reflux for 2 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / 1N HCl and dichloromethane / water. The organic layer was dried over Na2SO4 and filtered, and the solvent was removed under vacuum, thus allowing the imidazopyridazine (II)

For example, for

och3

NMR (400 MHz, DMSO-d 6): δ 7.69-6.79 (m, 6H, Ar), 3.75 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.35 (s, 2H CH2), 2.17 (s, 3H, CH3). MS (ES) m / z = 312 (MH +) HPLC = 90%

Yield = 60%

Example G: General method for the preparation of imidazopyridines (I, X = CO, R 3 or R 4 are substituted amino groups)

(II) a, x = co) 54

To a solution of (II) (1eq) in methanol was added a solution of (substituted) hydrazine (5 eq) in methanol. The mixture was stirred at reflux for 24 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / 1N HCl and dichloromethane / water. The organic layer was dried over Na2SO4 and filtered, and the solvent was removed under vacuum, thus allowing the imidazopyridazine (I). For example, for

1 H NMR (400 MHz, DMSO-d 6): δ 8.00 (bs, 1H, NH), 7.50-6.93 (m, 6H, Ar), 3.78 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.28 (s, 2H, CH2), 2.12 (bs, 2H, NH2). MS (ES) m / z = 312 (MH +) HPLC = 93%

Yield = 65%

Compounds 99-107 were prepared according to this methodology. 55

Example No. MH + (LCMS) Purity (UV) IUPAC NAME 99 355 100 [2- (4-fluoro-phenyl) -6-pyrrolidin-1-yl-imidazo [1,2- b] pyridazin-3-yl] - acetic acid hydrazide 100 361 100 [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] -3-pyridazin-3-yl] -hydrazide of acetic acid 101 312 93 [2- Acetic acid (4-Methoxy-phenyl) -6-methyl-imidazo [1,2-b] -3-pyridazin-3-yl] -hydrazide 102 317 99 [2- (4-chloro-phenyl) methyl-imidazo [1,2-b] -3-pyridazin-3-yl] -hydrazide 103 300 92 [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2- b] -3-pyridazin-3-yl] -hydrazide 104 282 99 (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazine-3-yl) -hydrazide - (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-morpholino-4-yl-acetamide 2- (6-Methyl- tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-piperidin-1-yl-acetamide 107 (6-Methyl-2-p-tolyl-imidazo [1,2- b] pyridazine- 3-yl) -acetic acid N ', N'-dimethylhydrazide 56

Composition example 1: 5 mg tablets

Active ingredient ΟΊ mg Colloidal silicon dioxide 0.6 mg Croscarmellose sodium 12.0 mg Talc 4.0 mg Magnesium stearate 1.5 mg Polysorbate 80 1.0 mg Lactose 75.0 mg Hydroxypropylmethylcellulose 3.0 mg Polyethylene glycol 4000 0.5 mg Titanium dioxide E171 Microcrystalline cellulose 1.5 mg q.s. to 125. C) mg

Composition example 2: 10mg capsules

Active Ingredient 10.0 mg Colloidal Silicon Dioxide 0.6 mg Crospovidone 12.0 mg Talc 4.0 mg Magnesium Stearate 1.5 mg Sodium Lauryl Sulfate 1.5 mg Lactose 77.0 mg Gelatin 28.5 mg Titanium Dioxide E171 1.5 mg Indigotin E132 0.02 mg Microcrystalline cellulose q.s. to 155 ° C.

Composition example 3: oral drops

Active ingredient 0.5 g Propylene Glycol 10.0 g Glycerin 5.0 g Saccharin sodium 0.1 g Polysorbate 80 1.0 g Lemon flavor 0.2 g Ethanol 25.00 ml Purified water q.s. to 100.0 ml of composition 4: 2.5 mg tablets Active ingredient 2.5 mg Colloidal silicon dioxide 0.6 mg Croscaramellose sodium 12.0 mg Talc 4.0 mg Magnesium stearate 1.5 mg Polysorbate 80 1.0 mg Lactose 75.0 mg Hydroxypropylmethylcellulose 3.0 mg Polyethylene glycol 4000 0.5 mg Titanium dioxide E171 Microcrystalline cellulose qb to 1.5 mg 125.0 mg 58

Composition example 5: 5 mg capsules

Active Ingredient ΟΊ mg Colloidal Silicon Dioxide 0.6 mg Crospovidone 12.0 mg Talc 4.0 mg Magnesium Stearate 1.5 mg Sodium Lauryl Sulfate 1.5 mg Lactose 77.0 mg Gelatin 28.5 mg Titanium Dioxide E171 1.5 mg Indigotin E132 0.02 mg Microcrystalline q.s. for compound 6: oral drops 155.0 mg Active ingredient 0.25 g

Propylene glycol 10. 0 g Glycerin 5.0 g Sodium saccharin 0.1 g Polysorbate 80 1.0 g Lemon flavor 0.2 g Ethanol 25.0 mL Purified water q.s. to 100. 0 mL

Claims (17)

Imidazo [1,2-pyridazine Compound of formula (I) wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, straight or branched (C 1 -C 6) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 3 -C 6) cycloalkyl, (C 2 -C 6) (C 1 -C 6) alkyl, hydroxy, -O (C 1 -C 6) alkyl, phenoxy, - (C 1 -C 6) alkyl, phenylthio, halogen, nitro, cyano, amino, (C 1 -C 6) alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, N - (C1 -C6) alkylpiperazinyl, phenyl optionally substituted with 1-5 groups Z and heteroaryl optionally substituted by 1-5 groups of Z; R 3 and R 4 are independently selected from the group consisting of hydrogen, straight or branched (C 1 -C 6) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 3 -C 6) cycloalkyl, (C 1 -C 6) (C1 -C6) alkylamino, -NH- (C1 -C6) alkyl-N-C1 -C6 dialkyl, pyrrolidinyl, morpholinyl, piperidinyl, -N- (C1 -C6) alkylpiperazinyl, -N- (C1 -C6) phenyl optionally substituted with 1-5 groups Z and heteroaryl optionally substituted by 1-5 groups of Z, or R3 and R4 may both form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted by 1 to 5 Z groups, with the proviso that R 3 and R 4 are not simultaneously hydrogen; X is selected from CO and SO2; Z is selected from the group consisting of straight or branched (C1 -C6) alkyl, (C2 -C6) alkenyl, (C2 -C6) alkynyl, (C3 -C6) cycloalkyl, (C2 -C6) haloalkyl, hydroxy, (C 1 -C 6) alkyl, phenoxy, - (C 1 -C 6) alkyl, phenylthio, halogen, nitro, cyano, amino, C 1 -C 6 alkylamino and C 1 -C 6 dialkylamino and pharmaceutically acceptable salts, polymorphs , hydrates, tautomers, stereoisomers and solvates thereof. A compound according to claim 1, wherein R1 is methyl, chloro, methoxy, ethoxy, phenylthio or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in the para-position for a methyl, halogen, methoxy , nitro, or trifluoromethyl. A compound according to any one of the preceding claims, wherein X is CO; R 3 is selected from the group consisting of hydrogen, (C 1 -C 6) -alkyl, phenyl optionally substituted with 1-5 of the groups Z, heteroaryl optionally substituted by 1-5 groups Z, amino, -NH- (C 1 -C 6) alkyl- N-C 1 -C 6 dialkyl, a pyrrolidinyl, 4-morpholinyl and 1-piperidinyl and R 4 is selected from the group consisting of hydrogen, linear (C 1 -C 6) alkyl, phenyl optionally substituted by 1-5 Z groups and heteroaryl optionally substituted by 1-5 groups of Z, or R 3 and R 4 may both form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted by 1-5 groups of Z; and Z is selected from the group consisting of methyl and methoxy. A compound according to any preceding preceding claim, wherein said compound is selected from the group consisting of: 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazine-3 -yl) -N, N-diethylacetamide; 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-chloro-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone; N, N-diethyl-2- (6-pyrrolidin-1-yl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; N, N-diethyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- [2- (4-Bromo-phenyl) -6-ethoxy-imidazo [1,2-b] pyridazin-3-yl] -1-morpholin-4-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-acetamide dibutyl; 2- [2- (4-Bromo-phenyl) -6-ethoxy-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; 2- [2- (4-Bromo-phenyl) -6-ethoxy-imidazo [1,2-b] pyridazin-3-yl] -N, N-diethylacetamide; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-morpholin-4-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-acetamide dibutyl; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -3 N, N-dipropyl-acetamide; 2- [2- (4-Bromo-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-diethylacetamide; 2- [2- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-diethylacetamide; 2- [2- (4-chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] -N, N-diethylacetamide; 2- [2- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] N, N-dipropyl-acetamide; N, N-Dibutyl-2 - [- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [4- (4-Chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] N, N-dipropylacetamide, N, N-Dibutyl-2 - [- 4-chloro-phenyl) -6-ethoxyimidazo [1,2-b] pyridazin-3-yl] acetamide; N, N-diethyl-2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropyl-acetamide; N, N-Dibutyl-2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-methoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethylacetamide; 2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholin-4-yl-ethanone; 2- (6-ethoxy-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 4 N, N-Diethyl-2- (6-methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropyl-acetamide; N, N-Dibutyl-2- (6-methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; N, N-Dibutyl-2- [2- (4-fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2- [2- (4-Fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; N, N-Dibutyl-2 - [- (4-fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2- [6-ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] N, N-dipropyl-acetamide; N, N-Dibutyl-2- [6-ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [6-ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; N, N-diethyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazine-3-yl) acetamide; 2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-methoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; 2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-diethylacetamide; 2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone; 2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-morpholino-4-yl-ethanone; 2- (6-ethoxy-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-piperidin-1-yl-ethanone; N, N-diethyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazine-3-yl-acetamide 2- (6-Methyl-2-p-tolyl-imidazo [ 3-yl) -N, N-dipropylacetamide; N, N-Dibutyl-2- (6-methyl-2-p-tolyl-imidazo [1,2- b] yl) acetamide 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -1-pyrrolidin-1-yl-ethanone: 2- (6-Methyl-2- 3-yl) -1-morpholino-4-yl-ethanone: 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -p-tolyl-imidazo [1,2- b] 3-yl) -1-piperidin-1-yl-ethanone; N, N-diethyl-2 - [- (4-fluoro-phenyl) -6-methyl-imidazo [1,2- b] pyridazine- 3-yl] acetamide; 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; N-diethyl-2 - [- (4-fluoro-phenyl) -6-methoxyimidazo [1,2-b] pyridazin-3-yl] acetamide; 2- [2- (4-Fluoro-phenyl) -6- 3-yl] -1-piperidin-1-yl-ethanone; 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridin- 3-yl] -N, N-diethylacetamide; 2- [6-Ethoxy-2- (4-fluoro-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1- pip eridin-1-yl-ethanone; 2- [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; 2- [2- (4-Fluoro-phenyl) -6-methoxy-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; N, N-diethyl-2 - [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2-2 [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropylacetamide; N, N-Dibutyl-2 - [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] acetamide; 2-2 [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2-2 [- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; N, N-diethyl-2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -N, N-dipropyl-acetamide; N, N-Dibutyl-2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -acetamide; 2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-piperidin-1-yl-ethanone; 2- [6-methoxy-2- (4-methoxy-phenyl) -imidazo [1,2-b] pyridazin-3-yl] -1-morpholino-4-yl-ethanone; 2 - {[2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetyl-propyl-amino} -ethyl ester; 1- (3,5-Dimethyl-piperidin-1-yl) -2-6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) ethanone; N-cyclopropylmethyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-propylacetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-7-thiazol-2-yl-acetamide; N, N-disopropyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; N-cyclohexyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-phenyl acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -NP-tolyl-acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-pyridin-2-yl-acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-pyridin-2-ylmethyl-acetamide; N- (3,5-Dimethyl-isoxazol-4-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide, N-cyclopentyl- 2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; N, N-Diallyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; N-cyclopropyl-2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N-hydroxy-2-yl-acetamide; N- (5-methylisoxazol-3-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; N- (4-methoxy-phenyl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; N- (3-methyl-isoxazol-5-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetamide; 2- (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) -N- [1,3,4] thiadiazol-2-yl-acetamide; [2- (4-fluoro-phenyl) -6-pyrrolidin-1-yl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; 8- [2- (4-Bromo-pheno) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; [2- (4-methoxy-phenyl) -6-methyl-imidazo [1,2-b] pyridazine-3-yl] -hydrazide; [2- (4-chloro-phenyl) -6-methyl-imidazo [1,2-b] pyridazine-3-yl] -hydrazide; [2- (4-Fluoro-phenyl) -6-methyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; (6-Methyl-2-phenyl-imidazo [1,2-b] pyridazin-3-yl] -hydrazide; pyridazin-3-yl) -N-morpholino-4-acetamide-1-yl) -2- (6-methyl-2-p-tolyl-imidazo [1,2- b] pyridazin- -yl-acetamide, and (6-Methyl-2-p-tolyl-imidazo [1,2-b] pyridazin-3-yl) acetic acid N ', N'-dimethylhydrazide. A process for the preparation of a compound of formula (I) as defined in claim 1, comprising the reaction of an intermediate (V): Br (V) with a substituted 3-aminopyridazine (VI): 9 wherein R 1, R 2, R 3, R 4 and X are as defined in any one of the preceding claims. A process for the preparation of a compound of formula (I) when X is CO as defined in claim 1, comprising a reaction of intermediate (II): Wherein R is a straight or branched (C 1 -C 6) alkyl group and R 4 and R 2 are as defined in (I), with a compound HNR 3 R 4 where R 3 and R 4 are as defined in (I). The process of claim 6, wherein R is methyl. 8. Imidazo [1,2-b] pyridazine Compound of formula (II): (II) as well as pharmaceutically acceptable salts thereof, wherein R is methyl, R 1 is methyl, chloro, methoxy, ethoxy, thiophene or 1-pyrrolidinyl group and R 2 is a phenyl group or a phenyl group substituted in the para-position methyl, halogen, methoxy, nitro or trifluoromethyl. A compound as defined in claim 1 for use in the treatment or prevention of diseases associated with modulation of the Î ± 1-GABAÎ ± receptor in a human or non-human mammal in need thereof. A compound as defined in claim 1 for use in the treatment or prevention of diseases associated with modulation of the Î ± -GABAÎ ± receptor in a human or non-human mammal in need thereof. in claim 1, for use of anxiety, epilepsy, in a human mammal or non-claim 1, for use or anesthesia in a mammal A compound as defined in the treatment or prevention of sleep or human insomnia disorders. at A compound as defined in inducing hypnosis of human or non-human sedation. A compound as defined in claim 1 for use in modulating the time required to induce sleep and its duration in a human or non-human mammal. A compound as defined in claim 1 for use in inducing muscle relaxation in a human or non-human mammal. 11 Use of a compound as defined in claim 1 for the manufacture of a medicament for treating or preventing diseases associated with modulation of the α-GABAÎ ± receptor in a human or non-human mammal in need thereof. Use of a compound as defined in claim 1 for the manufacture of a medicament for treating or preventing diseases associated with modulation of the α-GABAÎ ± receptor in a human or non-human mammal in need thereof. A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in claim 1 together with suitable amounts of pharmaceutical excipients or carriers. 8/30/10 12